Expression of interleukin-6 is downregulated by 17-(allylamino)-17-demethoxygeldanamycin in human prostatic carcinoma cells.
OBJECTIVE
Interleukin-6 (IL-6) is a pleiotropic cytokine that is associated with tumor metastasis and prostate cancer. We evaluated the mechanism and effect of 17-(allylamino)-17-demethoxygeldanamycin (17AAG), a novel inhibitor of heat shock protein 90 (Hsp90), on the IL-6 gene expression in human prostatic carcinoma (PC-3) cells.


METHODS
Quantitative IL-6 and IL-6 receptor (IL-6R) expressions were assessed using RT-PCR. The deregulation of 17AAG and phorbol 12-myristate 13-acetate (PMA) on the IL-6 gene was determined by ELISA and transient gene expression assays using an IL-6 reporter vector.


RESULTS
Although the IL-6R is ubiquitously expressed by prostatic epithelium cells, the IL-6 expression is only found in advanced prostatic carcinoma cells, such as PC-3 and DU145. Further studies using RT-PCR indicated that 17AAG downregulated the gene expression of IL-6. ELISA and the transient gene expression assay revealed that 17AAG blocked the stimulation of PMA of IL-6 gene expression in PC-3 cells. The PMA-induced IL-6 gene expression is dependent on the NF-kappaB response element. However, the effect of 17AAG appears to be mediated via a region located at -149 to +8 bp upstream of the transcriptional starting site of the IL-6 gene, and might not be through the NF-kappaB signaling pathway.


CONCLUSIONS
The present study reveals that IL-6 is transcriptionally downregulated in human prostatic carcinoma cells in response to 17AAG. This result suggests the presence of a novel Hsp90 mediation pathway that is involved in the deregulation on the transcription of the human IL-6 gene in human prostate cancer.
Tsui
Ke-hung
KH
Department of Urology, Chang Gung Memory Hospital, Kwei-Shan, Tao-Yuan, Taiwan, China.
Feng
Tsui-hsia
TH
Hsieh
Wen-chi
WC
Chang
Phei-lang
PL
Juang
Horng-heng
HH
D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005822:Genetic Vectors; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D000093242:Interleukin-6 Inhibitors
D016227:Benzoquinones; D004247:DNA; D018841:HSP90 Heat-Shock Proteins; D015850:Interleukin-6; D047029:Lactams, Macrocyclic; D000093242:Interleukin-6 Inhibitors; C112765:tanespimycin